2-Arylbenzothiazoline derivatives and their use in treating angina cordis

ABSTRACT

This invention relates to novel benzothiazoline derivatives of the formula [I] and salts thereof, ##STR1## wherein R 1  is formyl or lower alkanoyl; 
     R 2  is hydrogen, lower alkyl, lower alkoxy or nitro; 
     R 3  is hydrogen, lower alkyl, lower alkoxy or halogen; 
     A is lower alkylene; 
     B is --CO--(CH 2 ) m  -- or --CH(OH)--; 
     m is 0 or 1; and 
     when m is 0, R 3  is not hydrogen. 
     The compounds of this invention are useful for treatment of cardiovascular diseases.

DETAILED DESCRIPTION OF THE INVENTION

This invention relates to the compounds of the formula [I] and saltsthereof, ##STR2## wherein

R¹ is formyl or lower alkanoyl;

R² is hydrogen, lower alkyl, lower alkoxy or nitro;

R³ is hydrogen, lower alkyl, lower alkoxy or halogen;

A is lower alkylene;

B is --CO--(CH₂)_(m) --or --CH(OH)--;

m is 0 to 1; and

when m is 0, R³ is not hydrogen.

The term "lower alkanoyl" is intended to designate C₂ -C₆ alkanoylexemplified by acetyl, propanoyl and hexanoyl.

The term "halogen" is intended to designate fluorine, chlorine orbromine.

The term "lower alkyl" is intended to designate C₁ -C₆ alkyl exemplifiedby methyl, ethyl, propyl, butyl and hexyl.

The term "lower alkoxy" is intended to designate C₁ -C₆ alkoxyexemplified by methoxy, ethoxy, propoxy and hexyloxy.

The term "lower alkylene" is intended to designate straight or branchedC₁ -C₆ alkylene exemplified by methylene, ethylene, propylene, butyleneand hexylene.

The compounds of this invention are novel 2-phenylbenzothiazolinederivatives which are useful for treatment of cardiovascular diseases.The compounds of this invention have a specific structure where the2-position of the benzothiazoline ring is substituted by a phenyl grouphaving a heterocycle at the side chain.

Recently, we synthesized 2-phenylbenzothiazoline derivatives anddisclosed them in GB Pat. No. 2115815 published on Sept. 14, 1983.

We continuously studied the derivatives of 2-phenylbenzothiazoline inorder to find more useful compounds.

As the result of our precise examination, we found novel, very useful2-phenylbenzothiazoline derivatives represented by the formula [I].

The compounds of this invention possess superior plateletanti-aggregation effect and calcium antagonization. Iihibitors ofplatelet aggregation and calcium antagonists are used as therapeuticagents for cardiovascular diseases such as angina cordis, arrhythmia,thrombosis, etc., so the compounds of this invention are useful fortreatment of cardiovascular diseases.

The pharmacological tests prove the superior effect of the compounds ofthis invention.

The compounds of this invention can be prepared by the reaction ofhalide of the formula [II] with amine derivative of the formula [III].##STR3## wherein X is halogen.

The above reaction needs no specific conditions, and known methods whichare generally used for a reaction of amine derivatives with halides canbe used. For example, heating of a mixture of amine derivative andhalide, a reaction of amine derivative with halide in a presence of basesuch as triethylamine in an organic solvent.

The compounds of the formula [II] can be prepared according to thedisclosure of GB Pat. No. 2115815.

The compounds of the formula [III] can be prepared by known methodswhich are summarized as follows. ##STR4## The compounds of the formula[III], wherein B is --CH(OH)--, can be prepared by reduction of thecorresponding carbonyl compound.

The compounds [I] of this invention can be converted into acid salts.Said salts are obtained by usual methods using inorganic or organicacids. Examples of pharmaceutically acceptable salts of the compoundsare hydrochloric acid salt, sulfuric acid salt, phosphoric acid salt,lactic acid salt, maleic acid salt, fumaric acid salt, oxalic acid salt,succinic acid salt, citric acid salt, methanesulfonic acid salt,p-toluenesulfonic acid salt, etc.

The compounds of this invention have stereoisomers because of theexistence of one or more asymmetric carbon atoms, and these isomers areincluded in this invention.

Examples are shown below.

The assignments of the NMR spectra are made according to the numbers ofthe formula [IV] and aromatic protons, not assigned, are shown asaromatic H. When R² or R³ of the formula [I] is methoxy group, theformer is shown as --OCH₃ (P) and the latter is --OCH₃ (A). ##STR5##

EXAMPLE 1

3-Acetyl-2-[5-methoxy-2-[4-[4-(4-methoxybenzoyl)-1-piperidyl]butoxy]phenyl]benzothiazolineoxalate (compound 1)

A mixture of3-acetyl-2-[2-(4-chlorobutoxy)-5-methoxyphenyl]benzothiazoline (1.60 g)and 4-(4-methoxybenzoyl)piperidine (1.78 g) is stirred for 2 hours at110°-120° C. After cooling to room temperature, the mixture is dissolvedin chloroform (30 ml). The solution is washed with N hydrochloric acid,N sodium hydroxide solution and then saturated sodium chloride solution.The solution is dried over anhydrous magnesium sulfate and concentratedin vacuo. To the oily residue, a solution of oxalic acid (0.36 g) inmethanol (5 ml) is added to give 1.21 g (45%) of the titled compound.

mp 97°-103° C. (methanol-acetonitrile)

IR (KBr, cm⁻¹): 1664, 1597, 1465, 1377, 1276

NMR (DMSO-d₆, δ): 1.50-2.36 ##STR6## 2.22 (3H, s, --COCH₃), 2.73-3.85##STR7## 3.62 (3H, s, --OCH₃ (P) ), 3.88 (3H, s, --OCH₃ (A) ), 3.92-4.32(2H, m, -OCH₂ -), 6.36-6.73 (3H, m, C_(6'-H) and --CO₂ H×2), 6.73-7.39(8H, C₂ -H and aromatic H), 7.73-8.22

The following compound was prepared by the similar method as in Example1.

2-[2-[4-[4-(4-fluorobenzoyl)-1-piperidyl]butoxy]-5-methoxyphenyl]-3-formylbenzothiazoline fumarate(compound 2)

Yield 45%

mp 160°-161° C. (dec.), (methanol-acetonitrile) IR (KBr, cm⁻¹): 1712,1671, 1592, 1577, 1497, 1470, 1353, 1274, 1212, 1155, 1033, 744 NMR(DMSO-d₆, δ): 1.27-2.13 ##STR8## 2.30-3.50 3.58 (3H, s, --OCH₃ (P) ),3.80-4.27 (2H, m, --OCH₂ -), 6.33-8.20 (12H, m, C₂ -H and aromatic H),6.53 ##STR9## 8.23-8.67 (2H, br, --CO₂ H×2), 8.47 and 8.93 (1H, each s,--CHO)

EXAMPLE 2

3-Acetyl-2-(5-methoxy-2-[4-[4-(4-methylbenzoyl)-1-piperidyl]butoxy]phenyl]benzothiazolinemaleate (compound 3)

A mixture of 3-acetyl2-]2-(4-bromobutoxy)-5-methoxyphenyl]-benzothiazoline (1.31 g) and4-(4-methylbenzoyl)piperidine (1.22 g) is stirred for one hour at80°-90° C. After cooling to room temperature, the reaction procedure isfollowed by the similar procedure as in Example 1 to give 1.01 g (50%)of the titled compound.

mp (175°-178° C.

IR (KBr, cm⁻¹): 1671, 1604, 1577, 1493, 1465, 1379, 1275, 1208

NMR (DMSO-d₆), δ): 1.65-2.36 ##STR10## 2.27 (3H, s, --COCH₃), 2.42##STR11## 2.87-4.03 ##STR12## 3.67 (3H, s, -OCH₃ (P), 3.97-4.35 (2H, m,--OCH₂), 6.12 ##STR13## 6.46 (2H, d, J=2.4Hz, C₆ '-H), 6.65-7.40 (5H, m,aromatic H), 6.97 (1H, s, C₂ -H), 7.31 ##STR14## .sec 7.76-8.07 (1H, m,C₄ -H), 7.88 ##STR15##

The following compounds were prepared by the similar method as inExample 2.

3-Acetyl-2-[2-[4-[4-(4-chlorobenzoyl)-1-piperidyl]butoxy]-5-methoxyphenyl]benzothiazolinemaleate (compound 4)

Yield 90%

mp 177.5°-179.5° C.

IR (KBr, cm⁻¹): 1671, 1578, 1498, 1465, 1377, 1278, 1208 NMR (DMSO-d₆,δ): 1.66-2.32 ##STR16## 2.23 (3, s, --COCH₃), 2.75-4.05 ##STR17## 3.53(3H, s, --OCH₃ (P) ), 4.06 (2H, m, --OCH₂ -), 6.04 6.45 (1H, d, J=3.0Hz,C₆ '-H), 6.67-7.38 (5H, m, aromatic H), 6.93 (1H, s, C₂ -H), 7.45##STR18## 7.70-8.19 (1H, m, C₄ -H), 7.97 ##STR19##

3-Acetyl-2-[2-[4-[4-(α-hydroxybenzyl)-1-piperidyl]butoxy]5-methoxyphenyl]benzothiazolinemaleate (compound 5)

Yield 45%

mp 184°-188° C. (methanol-acetonitrile )

IR (KBr, cm⁻¹): 3370, 1638, 1571, 1487, 1476, 1457 NMR (DMSO-d₆, δ):0.83-2.06 ##STR20## 2.20 (3H, s, --COCH₃), 2.55-3.47 ##STR21## 3.54 (3H,s, --OCH₃ (P) ), 3.80-4.20 (2H, m, --OCH₂ --), 4.20-4.50 (1H, m,--CH(OH)--), 4.83-5.73 (1H, br, --OH), 5.97 ##STR22## 6,35-7.47 (12H, m,C₂ --H and aromatic H), 7.60-8.10 (1H m, C₄ -H)

EXAMPLE 3

3Acetyl-2-[2-[4-[4-(4-fluorobenzoyl)-1-piperidyl]butoxy]-5-methoxyphenyl]benzothiazolinemaleate (compound 6)

To a solution of3-acetyl-2[-2-(4-bromobutoxy)-5-methoxyphenyl]benzothiazoline (1.53 g)and 4-(4-fluorobenzoyl)piperidine (0.73 g) in ethanol (4 ml),triethylamine (0.35 g ) is added and the mixture is refluxed for 1.5hours. After cooling to room temperature, the mixture is dissolved inchloroform (20 ml). The solution is washed with N hydrochloric acid,water, saturated sodium hydrogen carbonate solution and then saturatedsodium chloride solution. The organic layer is dried over anhydrousmagnesium sulfate and concentrated in vacuo. The oily residue ispurified by silica gel column chromatography. The oily product (1.28 g)is dissolved in ethyl acetate (5 ml). A solution of maleic acid (0.26 g)in ethyl acetate (5 ml) is added to the solution to give 1.31 g (55%) ofthe titled compound.

mp 146°-149° C. (ethyl acetate-ethanol)

IR (KBr, cm⁻¹): 1671, 1594, 1494, 1462, 1375, 1348, 1274, 1232, 1208 NMR(DMSO-d₆, δ): 1.43-2.40 ##STR23## 2.23 (3H, s, --COCH₃), 2.77-3.87##STR24## 3.57 (3H, s, --OCH₃ (P) ), 3.87-4.36 (2H, m, --OCH₂ -), 6.03##STR25## 6.43 (1H, d, J=2.5 Hz, C₆ '-H), 6.60-7.22 (7H, m, aromatic H),7.19 (1H, s, C₂ -H), ##STR26## 7.60-8.12

The following compound was prepared by the similar method as in Example3.

3-Acetyl-2-[2-[4-(4-benzylcarbonyl-1piperidyl)butoxy]-5-methoxyphenyl]benzothiazolinemaleate (compound 7)

Yield 55%

mp 152°-154° C. (methanol)

IR (KBr, cm⁻¹): 3400, 1706, 1669, 1571, 1490, 1458

NMR (DMSO-d₆, δ): 0.82-2.36 ##STR27## 2.23 (3-H, s,--COCH₃), 2.58-3.76##STR28## 3.57 (3H, s, --OCH₃ (P) ), 3.79-4.26 (2H, m, --OCH₂ -), 3.89(2H s, --COCH₂ -), 6.03 ##STR29## 6.12 (1H, d, J=2.0Hz, C₆ '--H),6.26-7.36 (11H, m, C₂ -H and aromatic H), 7.58-8.08 (1H, m, C₄ -H)

EXAMPLE 4

3-Acetyl-2-[2-[3-[4-(4-fluorobenzoyl)-1-piperidyl]propoxy]-5-nitrophenyl]benzothiazoline(compound 8)

To a solution of3-acetyl-2-[2-(3-chloropropoxy)-5-nitrophenyl]benzothiazoline (3.93 g)in acetone (20 ml), sodium iodide (1.50 g) is added and the mixture isrefluxed for 2 hours. After cooling to room temperature, the reactionmixture is concentrated in vacuo to remove acetone. To the residue,benzene (20 ml) and 4-(4-fluorobenzoyl)piperidine (4.20 g) are added andthe mixture is refluxed for 9 hours.

After cooling to room temperature, chloroform (100 ml) is added to thereaction mixture. The mixture is washed with N hydrochloric acid, Nsodium hydroxide solution and then saturated sodium chloride solution.The solution is dried over anhydrous magnesium sulfate and concentratedin vacuo.

The oily residue is purified by silica gel column chromatography to give3.10 g (55%) of the titled compound.

mp 169°-172° C.

IR (KBr, cm⁻¹): 1665, 1588, 1508, 1489, 1460, 1449, 1376, 1330, 1262 NMR(DMSO-d₆, δ): 1.57-3.53 ##STR30## 2.33 (3H, m, --COCH₃), 4.25 (2H, t,J=6.0 Hz, --OCH₂ --), 6.83-8.30 (12H, m, C₂ -H and aromatic H)

Following compounds can be prepared by the similar method as in theabove examples.

3-Acetyl-2-[2-[4-[4-(4-fluorobenzoyl)-1-piperidyl]methoxy]-5-methoxyphenyl]benzothiazoline

3Acetyl-2-[2-[4-[4-(4-fluorobenzoyl)-1-piperidyl]propoxy]-5-methoxyphenyl]benzothiazoline

3Acetyl-2-[2-[4-[4-(4-fluorobenzoyl)-1-piperidyl]hexyloxy]-5-methoxyphenyl]benzothiazoline

3Acetyl-2-[2-[4-[4-(4-fluorobenzylcarbonyl)-1-piperidyl]butoxy]-5-methoxyphenyl]benzothiazoline

3-Acetyl-2-[2-[4-[4-(4-fluoro-α-hydroxybenzyl)-1-piperidyl]-butoxy]-5-methoxyphenyl]benzothiazoline

3-Acetyl-2-[2-[4-[4-(4-fluorobenzoyl)-1-piperidyl]-butoxy]-phenyl]benzothiazoline

3-Acetyl-2-[2-[4-[4-(4-fluorobenzoyl)-1-piperidyl]-butoxy]-5-methylphenyl]benzothiazoline

3-Acetyl-2-[5-ethyl-2-[4-[4-(4-fluorobenzoyl)-1-piperidyl]-butoxy]phenyl]benzothiazoline

2-[2-[4-[4-(4-Fluorobenzoyl)-1-piperidyl]-butoxy]-5-methoxyphenyl]-3-propanoylbenzothiazoline

3-Acetyl-2-[2-[4-[4-(4-methoxybenzylcarbonyl)-1-pipreidyl]-butoxy]-5-methylphenyl]-benzothiazoline

3-Acetyl-2-[2-[4-[4-(4-methylbenzylcarbonyl)-1-piperidyl]-butoxy]-5-nitrophenyl]-benzothiazoline

3-Acetyl-2-[2-[4-[4-(α-hydroxy-4-methoxybenzyl)-1-piperidyl]-butoxy]-5-methylphenyl]-benzothiazoline

3-Acetyl-2-[2-[4-[4-(α-hydroxy-4-methylbenzoyl)-1-piperidyl]-butoxy]-5-nitrophenyl]-benzothiazoline

Pharmacological Activities

Calcium antagonists have not only beneficial effects in the treatment ofmany diseases but also serve as valuable research tools to elucidateexcitation-contraction coupling in various muscule types (A.Fleckenstein, Ann. Rev. Pharmacol. 17, 149-166, 1977). Therefore, weexamined the calciumantagonistic activity of the compounds of thisinvention.

Pharmacological test I

The action potentials on the smooth muscles of uterus, teania coli andportal vein depend on calcium ion, and therefore these smooth musclepreparations are useful for screening of calciumantagonists. We measuredthe calciumantagonistic activity of the compounds by the method usingguineapig teania coli preparation.

Isolated guineapig teania coli was suspended in a 20 ml organ bath withKrebs solution at 32° C. and bubbled with 5% carbon dioxide in oxygen.After equilibration, the muscle was washed with Ca⁺⁺ -free Krebssolution, and when the muscle had relaxed to basal level, it wassuspended in Ca⁺⁺ -free-high-K Krebs solution.

The muscule was exposed to the test compounds for 5 minutes beforeaddition of CaCl₂, and the contraction evoked by CaCl₂ (3×10⁻⁴ M) wasrecorded isotonically. The calciumantagonistic activity was representedby the concentration of the test compound which elicited 50% inhibitionof Ca⁺⁺ -evoked contraction (IC₅₀).

As shown in Table 1, the compounds of this invention hadcalciumantagonistic activity.

Blood platelet plays an important role only in hemostasis but also inthrombosis. Platelet hyperaggregability leads to an increase in thenumber of circulating platelet aggregates, which may contribute towardthe development of cardiac arrhythmia, cardiac arrest or myocardialinfarction. These cardiovascular diseases can be prevented by inhibitionof platelet aggregation.

Therefore, we screened the influence of the test compounds on plateletaggregation in vitro, and found that they have antiaggregatory activity.

Pharmacological test II

Blood was obtained from an anesthetized rabbit using 0.1 volume of 3.8%sodium citrate as anticoagulant. Platelet rich plasma (PRP) was isolatedby centrifugation at 650 rpm for 10 minutes at room temperature. Afterpreincubation of PRP (0.25 ml) with various concentrations of the testcompounds (14μl) for 1 minute at 37° C., collagen (3μg/ml: finalconcentration) or ADP (3μM: final concentration) was added to induceaggregation and the aggregation profiles were monitored by RIKADENKIsix-channel aggregometer. The control experiment contained salineinstead of the test compound.

The antiaggregatory activity was represented by the concentration of thetest compounds which elicited 50% inhibition of the control response.

As shown in the Table 2, the compounds of this invention hadantiaggregatory activity.

                  TABLE 1                                                         ______________________________________                                        Calciumantagonistic activity                                                  compound No.    IC.sub.50 [M]                                                 ______________________________________                                        4               8.7 × 10.sup.-6                                         5               8.2 × 10.sup.-6                                         6               1.6 × 10.sup.-6                                         7               3.2 × 10.sup.-6                                         ______________________________________                                    

                  TABLE 2                                                         ______________________________________                                        Antiaggregation activity                                                      compound No.    IC.sub.50 [M]                                                 ______________________________________                                        3               3.2 × 10.sup.-6                                         4               3.2 × 10.sup.-6                                         6               2.9 × 10.sup.-7                                         ______________________________________                                    

The compounds can be administered either orally or parenterally. Thedosage forms are tablet, capsule, granule, powder, suppository,injection, etc. The dose is adjusted depending on symptom, dosage form,etc., but usual daily dosage is 1 to 5000 mg, preferably 10 to 1000 mg,in one or a few divided doses.

Examples of formulation are shown below.

Example of formulation

    ______________________________________                                        (a) Tablet                                                                    ______________________________________                                        compound No. 6           30     mg                                            lactose                  150    mg                                            crystalline cellulose    50     mg                                            calcium carboxymethylcellulose                                                                         7      mg                                            magnesium stearate       3      mg                                            total                    240    mg                                            compound No. 6           50     mg                                            lactose                  120    mg                                            crystalline cellulose    60     mg                                            calcium carboxymethylcellulose                                                                         7      mg                                            magnesium stearate       3      mg                                            total                    240    mg                                            ______________________________________                                    

The tablets may be treated with the common film-coating and further withsugar-coating.

    ______________________________________                                        (b) Granule                                                                   compound No. 6         30     mg                                              polyvinylpyrrolidone   25     mg                                              lactose                385    mg                                              hydroxypropylcellulose 50     mg                                              talc                   10     mg                                              total                  500    mg                                              (c) Powder                                                                    compound No. 6         30     mg                                              lactose                500    mg                                              starch                 440    mg                                              colloidal silica       30     mg                                              total                  1000   mg                                              (d) Capsule                                                                   compound No. 6         30     mg                                              lactose                102    mg                                              crystalline cellulose  56     mg                                              colloidal silica       2      mg                                              total                  190    mg                                              ______________________________________                                    

What we claim is:
 1. A compound of the formula, ##STR31## wherein R¹ isformyl or lower alkanoyl;R² is hydrogen, lower alkyl, lower alkoxy ornitro; R³ is hydrogen, lower alkyl, lower alkoxy or halogen; A is loweralkylene; B is --CO--(CH₂)_(m) --or --CH(OH)--; m is 0 or 1; and when mis 0, R³ is not hydrogen, or a non-toxic acid addition salt thereof. 2.The compound as in claim 1, wherein R¹ is acetyl.
 3. The compound as inclaim 1, wherein R² is methoxy or nitro.
 4. The compound as in claim 1,wherein R³ is hydrogen, methyl, methoxy, fluorine or chlorine.
 5. Thecompound as in claim 1, wherein A is --(CH₂)₃ --or --(CH₂)₄ --.
 6. Acompound of the formula, ##STR32## wherein R¹ is formyl or acetyl;R² ismethoxy or nitro; R³ is methyl, methoxy, chlorine or fluorine; A is--(CH₂)₃ -or --(CH₂)₄ --; and B is --CO--,or a non-toxic acid additionsalt thereof.
 7. A compound of the formula, ##STR33## wherein R¹ isacetyl;R² is methoxy; R³ is hydrogen; A is --(CH₂)₄ --; B is--CO--(CH₂)_(m) --or --CH(OH)--; and m is 1,or a non-toxic acid additionsalt thereof. 8.3-Acetyl-2-[5-methoxy-2-[4-[4-(4-methoxybenzoyl)-1-piperidyl]butoxy]phenyl]benzothiazolineas in claim
 6. 9.3-Acetyl-2-[2-[4-[4-(4-chlorobenzoyl)-1-piperidyl]butoxy]-5-methoxyphenyl]benzothiazolineas in claim
 6. 10.3-Acetyl-2-[2-[4-[4-(4-fluorobenzoyl)-1-piperidyl]butoxy]-5-methoxyphenyl]benzothiazolineas in claim
 6. 11.3-Acetyl-2-[2-[4-[4-(α-hydroxyphenyl)-1-piperidyl]butoxy]-5-methoxyphenyl]benzothiazolineas in claim
 7. 12.3-Acety-2-[2-[4-(4-benzylcarbonyl-1-piperidyl)butoxy]-5-methoxyphenyl]benzothiazolineas in claim
 7. 13. A pharmaceutical composition comprising (i) acompound as in claim 1 in an amount sufficient for treatment for anginacordis, arrhythmia and thrombosis and (ii) at least one pharmaceuticallyacceptable excipient.
 14. A method of treatment for angina cordis,arrhythmia and thrombosis which comprises administering a compositioncomprising a compound as in claim 1 and at least one pharmaceuticallyacceptable excipient.